Process for production of 2-acetylbenzo[b]thiophene

ABSTRACT

A process for production of 2-acetylbenzo[b]thiophene represented by the formula (I): ##STR1## comprising the steps of: (1) reacting 2-halogenobenzaldehyde represented by the formula (II): ##STR2## wherein X represents a halogen atom, with a compound represented by the formula (III): 
     
         H.sub.i S.sub.j M.sub.k 
    
     wherein M represents an alkali metal, i represents zero or 1, j represents an integer of at least 1, and k represents an integer of 1 or 2, and preferably also with sulfur; and 
     (2) reacting the reaction product with a monohalogenoacetone represented by the formula (IV) ##STR3## wherein X 1  represents a halogen atom.

This application is a divisional of Ser. No. 07/997,932, filed Dec. 29,1992, now U.S. Pat. No. 5,266,705.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for production of2-acetylbenzo[b]thiophene, which is useful as an intermediate for thesynthesis of an antiinflammatory agent, Zileuton.

2. Related Art

As a process for production of 2-acetylbenzo[b]thiophene, a processcomprising reacting benzo[b]thiophene with a strong base such as butyllithium, followed by reaction with acetylchloride is described in J.Chem. Soc. Comun., 3447 (1977). In this process, however, the reactionwith butyllithium must be carried out at a low temperature and thereforean operation is industrially difficult, and moreover the startingmaterial, benzo[b]thiophene is expensive.

Comptes rendus, vol. 234, 736 describes a process for production of2-acetylbenzo[b]thiophene by reacting 2-mercaptobenzaldehyde withchloroacetone. However, in this process, the starting material,2-mercaptobenzaldehyde is difficult to synthesize, and unstable, andtherefore handling the same is not convenient.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for production of2-acetylbenzo[b]thiophene, using an industrially applicable operationand industrially available starting material.

More specifically, the present invention provides a process forproduction of 2-acetylbenzo[b]thiophene represented by the formula [I]:##STR4## comprising the steps of:

(1) reacting 2-halogenobenzaldehyde represented by the formula (II):##STR5## wherein X represents a halogen atom, with a compoundrepresented by the formula (III):

    H.sub.i S.sub.j M.sub.k

wherein M represents an alkali methal, i represents zero or 1, jrepresents an integer of at least 1, and k represents an integer of 1 or2; and

(2) reacting the reaction product with a monohalogenoacetone representedby the formula (IV): ##STR6## wherein X¹ represent a halogen atom.

The present invention further provides a process for production of2-acetylbenzo[b]thiophene comprising the steps of:

(1) reacting 2-halogenobenzaldehyde (II) with a compound represented bythe formula (III) and sulfur; and

(2) reacting the reaction product with a monohalogenoacetone (IV).

PREFERRED EMBODIMENT FOR CARRYING OUT THE INVENTION

The present process is preferably carried out in an aprotic polarsolvent, such as N-methypyrrolidone, N-octylpyrrolidone,1,3-dimethylimidazolidinone, diethylacetamide, dimethylacetamide,dimethylformamide, dimethylsulfoxide, sulforan, tetramethylurea,hexamethylphosphoric triamide, N-methyl-N-phenylformamide or the like,or mixtures thereof. Moreover, according to the present invention, amixed solvent comprising one or more than one of the above-mentionedaprotic polar solvents and other inert solvents miscible with theaprotic polar solvent can be used. Such solvents include benzene,toluene, xylenes, chlorobenzene, dichlorobenzenes and the like.

The amount of solvent is not critical as long as it provides a viscositythat allows agitation of the reaction mixture, such as a slurry, butshould preferably be 100 ml to 3000 ml per 1 mole of2-halogenobenzaldehyde.

In an embodiment (the first embodiment) of the first reaction (1),2-halogenobenzaldehyde represented by the above-mentioned formula (II)is reacted with a compound represented by the above-mentioned formula(III). In the formula (II), the halogen as the substituent X may be anyhalogen, such as fluorine, chlorine, bromine or iodine, but preferably Xrepresents chlorine atom, because chlorobenzaldehyde is industriallyavailable and not expensive. The compound represented by theabove-mentioned formula (III) is, for example, potassium sulfide (K₂ S),sodium sulfide (Na₂ S), potassium hydrogen sulfide (KSH), sodiumhydrogen sulfide (NaSH), potassium polysulfide, sodium polysulfide, orthe like.

The amount of compound (III) is preferably 0.5 to 10 moles and morepreferably 1 to 3.5 moles, per 1 mole of 2-halogenobenzaldehyde (II).

In the formula (III) the integer j is for example 1 to 10, and usually 1to 6.

The first reaction is usually carried out at a temperature between 0° C.and the boiling point of the solvent used, and preferably between 0° C.and 50° C. The end point of the reaction may be confirmed by thedisappearance of 2-halogenobenzaldehyde as determined by gaschromatography, and usually the reaction time is about 3 to 24 hours.

The first reaction may be carried out by adding 2-halogenobenzaldehyde(compound II) to a compound represented by the formula (III), or byadding the compound (III) to 2-halogenobenzaldehyde (II), but preferablyby adding 2-halogenobenzaldehyde (II) to compound (III).

In another embodiment (the second embodiment) of the first reaction (1),2-halogenobenzaldehyde represented by the formula (II) is reacted with acompound represented by the formula (III) and sulfur. The compound (II),the compound (III), amounts of the compounds (II) and (III), and otherconditions such as the order for adding reactants are the same as thosedescribed for the first embodiment of the first reaction.

In the second embodiment, the compound (III) and sulfur are preferablymixed in an aprotic polar solvent at a temperature between a roomtemperature and about 50° C. for 0.5 to 3 hours with agitation, prior toreaction with the compound (II). This reaction provides a polysulfide ofmetal M.

Although the present invention may use either the first embodiment orthe second embodiment in the first reaction, the second embodimentprovides the final product 2-acetylbenzo[b]thiophene, in a yield higherthan the first embodiment, and therefore the second embodiment ispreferable.

In the second reaction, the product of the first reaction is reactedwith a monohalogenoacetone represented by the above-mentioned formula(IV).

In the formula (IV), X¹ may be any halogen, such as fluorine, chlorine,bromine or the like, but preferably, the monohalogenoacetone ismonochloroacetone or monobromoacetone.

The amount of monohalogeneacetone is usually 0.5 to 10 moles andpreferably 1 to 2 moles per 1 mole of 2-halogenobenzaldehyde.

Since the second reaction is exothermic, during the reaction, thereaction mixture is preferably cooled to maintain a temperature between0° C. and 50° C. The reaction time is usually 1 to 16 hours depending onthe reactants, solvent, reaction temperature and other conditions.

It is considered that the first reaction provides 2-mercaptobenzaldehydeas a main product, and in an embodiment of the present invention, the2-mercaptobenzaldehyde is once recovered from the reaction mixture ofthe first reaction, and the isolated 2-mercaptobenzaldehyde is used inthe second reaction.

However, since 2-mercaptobenzaldehyde is unstable and difficult toisolate in a good yield, according to a preferred embodiment of thepresent invention, monohalogenoacetone is added to the reaction mixtureof the first reaction after completing the first reaction, and then thesecond reaction is carried out in the same reaction medium and reactionvessel as the first reaction. Alternatively, the reaction mixture of thefirst reaction may be added to monohalogenoacetone.

In the embodiment wherein the first and second reactions are carried outin the same reaction medium without isolating 2-mercaptobenzaldehyde thetotal reaction time is usually 4 to 43 hours.

The final product, 2-acetylbenzo[b]thiophene can be obtained with a highdegree of purity by crystallization from a mixture of cyclohexane or analcohol, such as isopropanol, and water, or by distillation.

According to the present invention, 2-acetylbenzo[b]thiophene can beindustrially produced using stable and inexpensive starting materials,by a simple operation.

EXAMPLES

The present invention is described in detail by the Example hereinafter.

Example 1

To a 200 ml four-necked flask, equipped with a stirrer, a thermometerand a reflux condenser, were added 9.63 g (68 m moles) of sodiumtrisulfide and 50 ml of N,N-diethylacetamide, and the mixture wasstirred at room temperature for one hour. To the reaction mixture wasdropwise added 5.50 g (60 m moles) of chloroacetone, and the reactionmixture was stirred at room temperature for 16 hours. After finishingthe reaction, 100 ml of diethyl ether and 100 ml of water were added tothe reaction mixture, and the pH value of the aqueous layer was adjustedto higher than 11 with a sodium hydroxide aqueous solution, andextracted with diethyl ether. The diethyl ether extract was twice washedwith water, and concentrated under a reduced pressure to obtain 7.0 g of2-acetylbenzo[b]thiophene (yield 79%). The purity of the product is 95%as determined by gas chromatography.

Example 2 to 5

The same procedure as described in Example 1 was repeated except thatthe compound (III) and reaction medium (solvent) were changed as shownin Table 1.

                  TABLE 1                                                         ______________________________________                                        Example                                                                              2-Halogeno-                    Yield                                   No.    benzaldehyde                                                                             Compound (III)                                                                            Solvent (%)                                     ______________________________________                                        2      2-chloro-  Sodium sulfide                                                                            N-methyl-                                                                             58                                             benzaldehyde           pyrrolidone                                     3      2-chloro-  Potassium   N-methyl-                                                                             60                                             benzaldehyde                                                                             sulfide     pyrrolidone                                     4      2-chloro-  Sodium tetra-                                                                             N-methyl-                                                                             75                                             benzaldehyde                                                                             sulfide     pyrrolidone                                     5      2-chloro-  Sodium      N-methyl-                                                                             57                                             benzaldehyde                                                                             hydrogensulfide                                                                           pyrrolidone                                     ______________________________________                                    

Example 6

To a 200 ml four-necked flask, equipped with a stirrer, a thermometerand a reflux condenser, were added 11.7 g (150 m moles) of anhydroussodium sulfide, 3.2 g (100 m moles) of sulfur and 100 ml ofN-methylpyrrolidone, and the mixture was stirred at room temperature forone hour. To the reaction mixture was dropwise added 14.1 g (100 mmoles) of 2-chlorobenzaldehyde, and the mixture was stirred at roomtemperature for 12 hours. To the reaction mixture, was dropwise added11.1 g (120 m moles) of chloroacetone with cooling, and the reactionmixture was stirred at room temperature for 6 hours. After finishing thereaction, 100 ml of diethyl ether and 100 ml of water were added to thereaction mixture, and pH value of the aqueous layer was adjusted tohigher than 11 with a sodium hydroxide aqueous solution, and extractedwith diethyl ether. The diethyl ether extract was washed twice withwater, and the diethyl ether layer was concentrated under a reducedpressure to obtain 13.0 g of 2-acetylbenzo[b]thiophene (yield 74%).Purity of the product was 95% as determined by gas chromatography.

Example 7

The same procedure as described in Example 6 was repeated except thatsulfur was not added. 8.6 g of 2-acetylbenzo[b]thiophene was obtained(yield 51%). The purity of the product was 95% as determined by gaschromatography.

Examples 8 to 14

The same procedure as described in Example 6 was repeated except that2-halogenobenzaldehyde, the compound (III)+ sulfur, and the reactionmedium (solvent) shown in Table 2 were used.

                  TABLE 2                                                         ______________________________________                                        Exam-            Compound                                                     ple   2-Halogeno-                                                                              (III) +               Yield                                  No.   benzaldehyde                                                                             sulfur       Solvent  (%)                                    ______________________________________                                         8    2-chloro-  sodium sulfide +                                                                           1,3-dimethyl                                                                           76                                           benzaldehyde                                                                             sulfur       imida-                                                                        zolidinone                                       9    2-chloro-  sodium sulfide +                                                                           N,N-diethyl                                                                            91                                           benzaldehyde                                                                             sulfur       acetamide                                       10    2-chloro-  sodium sulfide +                                                                           N,N-dimethyl                                                                           71                                           benzaldehyde                                                                             sulfur       formamide                                       11    2-chloro-  sodium sulfide +                                                                           dimethyl 74                                           benzaldehyde                                                                             sulfur       sulfoxide                                       12    2-chloro-  sodium sulfide +                                                                           N,N-dimethyl                                                                           78                                           benzaldehyde                                                                             sulfur       acetamide                                       13    2-bromo-   sodium sulfide +                                                                           N-methyl-                                                                              60                                           benzaldehyde                                                                             sulfur       pyrrolidone                                     14    2-fluoro-  sodium sulfide +                                                                           N-methyl-                                                                              66                                           benzaldehyde                                                                             sulfur       pyrrolidone                                     ______________________________________                                    

Example 15

The same procedure as described in Example 6 was repeated except that amixture of N,N-diethylacetamide and toluene (1:1 by volume) was used inplace of N-methyl pyrrolidone and the reaction temperature was 60° C. Asa result, the yield of 2-acetylbenzo[b]thiophene was 89%.

We claim:
 1. A process for production of 2-acetylbenzo[b]thiophenerepresented by the formula (I): ##STR7## comprising the steps of: (1)reacting 2-halogenobenzaldehyde represented by the formula (II):##STR8## wherein X represents a halogen atom, with a compoundrepresented by the formula (III):

    H.sub.i S.sub.j M.sub.k

wherein M represents an alkali metal, i represents zero or 1, jrepresents 1, and k represents an integer of 1 or 2; and (2) reactingthe reaction product with a monohalogenoacetone represented by theformula (IV): ##STR9## wherein X¹ represents a halogen atom, withoutisolation of the intermediate produced by step (1), the first and secondreactions being carried out in an aprotic polar solvent.
 2. A processaccording to claim 1, wherein the first reaction (1) and the secondreaction (2) are sequentially carried out in the same reaction vesselwithout isolating the intermediate compound from the first reaction. 3.A process according to claim 1, wherein the aprotic polar solvent isN,N-diethylacetamide or N-methylpyrrolidone.